Arsenic is an important environmental carcinogen that affects millions of people worldwide through[unreadable] contaminated water supplies. Although arsenic induces various human cancers including skin, lung, bladder,[unreadable] kidney and liver, the carcinogenic mechanism remains unknown. With the funding support of this grant, the[unreadable] applicant has shown, for the first time, that arsenic is a potent gene and chromosomal mutagen in[unreadable] mammalian cells and induces mostly multilocus deletions. These findings provide the first direct link between[unreadable] chromosomal abnormalities that have frequently been demonstrated in vitro and carcinogenicity in vivo.[unreadable] Furthermore, our recent data have shown that mitochondria are a primary target in mediating arsenicinduced[unreadable] genotoxicity. The overall goal of this application is to elucidate the contribution of mitochondrial DNA[unreadable] mutations and cell signaling pathways in mediating the genotoxicity and apoptosis of arsenic in mammalian[unreadable] cells. To achieve this goal, a series of eight inter-related specific aims are proposed to address the four[unreadable] testable hypotheses. The human-hamster hybrid (A-L) cell assay will be used to ascertain the role of[unreadable] mitochondrial DNA mutations and mitochondrial functions in modulating arsenic (sodium arsenite and[unreadable] methylated arsenic species) induced mutations at the CD59 locus. Since mitochondrial damage is often[unreadable] associated with induction of cell death, human melanocytes and melanoma cells will be used to define the[unreadable] cell signaling pathways involved in mediating arsenic-induced apoptosis. There is a profound necessity to[unreadable] develop effective treatment strategy for this often fatal cancer. Furthermore, there is considerable interaction,[unreadable] both conceptually and in shared materials, between this project and that of Projects 2, 3 and 4. A better[unreadable] understanding of the genotoxic and apoptotic mechanisms of arsenic will provide better interventional[unreadable] approach both in the treatment and prevention of arsenic-induced human diseases.